Despite 25 years of NIH funded investigation on interstitial cystitis/bladder pain syndrome (IC/BPS) focused on the bladder, no meaningful new therapies have emerged and the pathophysiology remains obscure. IC/BPS afflicts 3 to 8 million women in the US with chronic pain, voiding dysfunction, sleep deprivation and other co- morbid conditions that interfere with relationships and employment at a cost of over $100M/yr. We have assembled a unique group of accomplished clinicians and scientists with diverse expertise that spans clinical pelvic pain, neuroimaging, brainstem connectivity, pain modulation, autonomic disorders and heart rate variability across 3 sites. Based on the first cycle findings of the ICEPAC study (Interstitial Cystitis - Elucidation of Psychophysiologic and Autonomic Characteristics), this innovative proposal aims to understand whether correcting autonomic nervous system abnormalities and the underlying brain pathways can change the course of chronic pelvic pain in women suffering from IC/BPS and myofascial pelvic pain syndrome (MPP). Prior findings from ICEPAC showed that these two disorders differ in their physiology and psychology. Yet, they are often confused clinically. ICEPAC found that the majority of women have both disorders together, while a large minority has one. Careful phenotyping, however, demonstrates a unique autonomic profile for IC/BPS, with reduced autonomic nervous system responsiveness (ANS-R) measured by heart rate variability. The current proposal therefore aims to determine if ANS-R impairment may cause IC/BPS and its symptoms. The first aim will assess whether changes in ANS-R precede or follow changes in disease state over 24 weeks in subjects with IC/BPS and MPP. The second aim will evaluate how the disease state responds to direct modification of ANS-R using a medication intended to improve ANS-R by reducing sympathetic tone (the beta-blocker metroprolol vs placebo). We expect better ANS-R to improve response of IC/BPS more than it improves response of MPP to standard treatments. The third aim will determine whether ANS-R changes are reflected in connectivity between a high level control area in the brain, the prefrontal cortex, and the periaqueductal gray, a brainstem switch that controls pain and autonomic functions including blood pressure, heart rate and bladder function. We expect that stronger connections will reflect higher ANS-R when IC/BPS improves. This proposal is innovative in that 1) we are the first group to rigorously parse the phenotypes of IC/BPS and MPP, enabling assessment of specific disease markers; and 2) this is the first longitudinal prospective study assessing ANS-R in any type of chronic pain to assess possible causality. Findings from this study may provide entirely new insight into the relationship of autonomic and pain pathways. If the hypothesis that poor ANS-R may cause or maintain chronic pain states proves correct, entirely new avenues of chronic pain treatment may open, not just in chronic pelvic pain, but in other types of pain as well. Importantly, we would gain completely new insight into the interaction between these very complex neural systems.